Preservative free brimonidine and timolol solutions

ABSTRACT

The present invention is directed to preservative-free solutions of brimonidine and timolol for lowering intra-ocular pressure and treatment of glaucoma.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/245,026, filed Jan. 10, 2019, which is a continuation of U.S. patentapplication Ser. No. 13/812,599, filed Jan. 28, 2013, now U.S. Pat. No.10,213,431, issued Feb. 26, 2019, which is a national phase applicationunder 35 U.S.C. § 371 of PCT Patent Application No. PCT/US2011/045656,filed Jul. 28, 2011, which claims priority to U.S. Provisional PatentApplication Ser. No. 61/368,681, filed on Jul. 29, 2010, each of whichare incorporated herein by reference in their entireties and serve asthe basis of a priority and/or benefit claim for the presentapplication.

FIELD OF THE INVENTION

The present application is directed to preservative-free formulations ofbrimonidine and timolol.

BACKGROUND OF THE INVENTION

Brimonidine tartrate is a selective and potent alpha-2 adrenergicagonist. Brimonidine lowers intraocular pressure by reducing aqueoushumor production and increasing uveoscleral outflow. Timolol maleate isa non-selective beta adrenergic receptor blocking agent. Currentlymarketed brimonidine and timolol combination ophthalmic solution withpreservative is indicated for the reduction of elevated intraocularpressure (IOP) in patients with glaucoma or ocular hypertension whorequire adjunctive or replacement therapy due to inadequately controlledIOP.

Use of preservative containing eye drops has been implicated in thedevelopment or worsening of ocular surface disease. Management of openangle glaucoma and ocular hypertension require long term treatment witheye drops containing preservatives. Symptoms and signs of ocular surfacedisease such as ocular surface breakdown, irritation, burning, foreignbody sensation, dryness, inadequate quantity of tears, etc. areprevalent in a large proportion of patients with open angle glaucoma andocular hypertension.

Compared to eye drops preserved with benzalkonium chloride,preservative-free eye drops induce significantly fewer ocular symptomsand signs of irritation in patients, such as pain or discomfort,hyperemia, foreign body sensation, stinging or burning, and dry eyesensation.

Patients experiencing hypersensitivity reactions with benzalkoniumchloride cannot use a commercial brimonidine and timolol productscontaining benzalkonium chloride which is preserved even with 0.005% w/vbenzalkonium chloride. Benzalkonium chloride also may be absorbed by thesoft contact lenses therefore patients wearing soft contact lenses areadvised to remove lenses prior to administration and wait at least 15minutes before reinserting them.

SUMMARY OF THE INVENTION

The present invention is directed to a brimonidine and timolol solutionswithout benzalkonium chloride or other preservatives which will besuperior from a safety & tolerability standpoint while maintainingand/or improving its efficacy of IOP lowering and be available for useby patients hypersensitive to benzalkonium chloride and be convenientfor patients wearing soft contact lenses.

Brimonidine and timolol ophthalmic solution without preservative is aclear, greenish-yellow, isotonic, sterile solution. The drug productcontains brimonidine and timolol as the active ingredients. The inactiveingredients are tonicity and buffer agents, and purified water. Suitablebuffers such as sodium phosphate dibasic heptahydrate and citric acidmonohydrate and suitable tonicity agents such as sodium chloride may beincluded. The final solution would be an aqueous solution having a pHvalue within the range of about 6.5 to about 7.3, preferably 6.9 andosmolality in range of 260-220 mOsmol/kg.

The compositions of the present invention may be generally madeaccording to the teachings of U.S. Pat. No. 7,323,463 which is herebyincorporated by reference in its entirety.

Certain embodiments of the present invention are described below:

-   1) A preservative free brimonidine and timolol composition for    lowering intraocular pressure in a human patient comprising the    following formulation: about 0.2% w/v brimonidine; about 0.5% w/v    timolol; about 2.15% w/v sodium phosphate dibasic heptahydrate;    water and at a pH of about 6.9.-   2) A preservative free brimonidine and timolol composition for    lowering intraocular pressure in a human patient comprising the    following formulation: 0.2% w/v brimonidine; 0.5% w/v timolol; about    2.15% w/v sodium phosphate dibasic heptahydrate; hydrochloric acid,    sodium hydroxide, and water and at a pH of about 6.9.-   3) The preservative free composition of paragraphs 1-2 wherein the    timolol is timolol maleate at 0.68% w/v and brimonidine is    brimonidine tartrate.-   4) A composition as described in Table 1.-   5) The composition of any of paragraphs 1-4 wherein the composition    is a solution and is useful for treating glaucoma.-   6) The composition of any of paragraphs 1-4 wherein the composition    is a solution and is contained in a unit dose kit form.-   7) The composition of any of paragraphs 1-4 wherein the composition    is applied at least once a day.-   8) The composition of paragraph 2 wherein the composition is applied    twice a day.-   9) The composition of paragraphs 1 or 2 wherein the composition has    greater bioavailability of brimonidine and timolol in the eye of the    patient with fewer side-effects than brimonidine and timolol    preserved with benzalkonium chloride.-   10) The composition of paragraphs 1 and 2 wherein the composition is    contained in a multi-dose vial which has anti-preservative    properties such as metal-ions imbedded in its dispensing tip.-   11) The composition of paragraph 12 wherein the metal ions are    silver ions.

DETAILED DESCRIPTION OF THE INVENTION

A brimonidine and timolol ophthalmic formulation of the presentinvention without preservative is shown in Table-1.

TABLE 1 Example of brimonidine and timolol ophthalmic solution withoutpreservative according to the present invention: Ingredients Units GradeAmount Brimonidine Tartarate % w/v N/A 0.2 Timolol Maleate % w/v USP/Ph0.68 Eur Sodium Phosphate % w/v USP 2.15 Dibasic Heptahydrate SodiumPhosphate % w/v USP 0.43 Monobasic Monohydrate Hydrochloric Acid % w/vUSP/Ph pH 6.9 Eur Sodium Hydroxide % w/v USP/Ph pH 6.9 Eur PurifiedWater/ Q.S. USP/Ph QS Water for injection Eur

The present invention is directed to formulations of brimonidine andtimolol without benzalkonium chloride as a preservative. As a result ofthe removal of benzalkonium chloride, the present invention results inthe same or greater bioavailability of the active ingredientsbimatoprost and timolol in the eye without the unwanted side-effectsassociated with the preservative benzalkonium chloride which willimprove efficacy of the product in lowering IOP per dosage unit,superior patient compliance and with fewer side-effects such ashyperemia. Other side effects which may be avoided include asthenia,blepharitis, corneal erosion, depression, epiphora, eye discharge, eyedryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelidpruritus, foreign body sensation, headache, hypertension, oral dryness,somnolence, superficial punctate keratitis, and visual disturbance.

1) A preservative free brimonidine and timolol composition for loweringintraocular pressure in a human patient comprising the followingformulation: about 0.2% w/v brimonidine; about 0.5% w/v timolol; about2.15% w/v sodium phosphate dibasic heptahydrate; water and at a pH ofabout 6.9. 2) A preservative free brimonidine and timolol compositionfor lowering intraocular pressure in a human patient comprising thefollowing formulation: 0.2% w/v brimonidine; 0.5% w/v timolol; about2.15% w/v sodium phosphate dibasic heptahydrate; hydrochloric acid,sodium hydroxide, and water and at a pH of about 6.9. 3) Thepreservative free composition of claim 1 wherein the timolol is timololmaleate at 0.68% w/v and brimonidine is brimonidine tartrate. 4) Acomposition as described in Table
 1. 5) The composition of claim 1wherein the composition is a solution and is useful for treatingglaucoma. 6) The composition of claim 1 wherein the composition is asolution and is contained in a unit dose kit form. 7) The composition ofclaim 1 wherein the composition is applied at least once a day. 8) Thecomposition of claim 2 wherein the composition is applied twice a day.9) The composition of claim 1 wherein the composition has greaterbioavailability of brimonidine and timolol in the eye of the patientwith fewer side-effects than brimonidine and timolol preserved withbenzalkonium chloride. 10) A method of lowering IOP in a patientsuffering from elevated IOP by administering the composition of claim 1.